crossing96/oncoscreening huggingface dataset:
Co-targeting the CD73-adenosinergic axis enhances the anti-tumor efficacy of anti-PD-L1 immunotherapy in bladder cancer.	Immune checkpoint inhibitors have significantly improved advanced bladder cancer care, but resistance remains a significant challenge. Adenosinergic signaling is an immunosuppressive mechanism hindered by tumor cells to escape from immune surveillance and suppress antitumor immune responses. Herein, we investigate whether co-targeting the adenosine pathway can modulate tumor immunity and enhance the efficacy of anti-PD-L1 therapy in an orthotopic murine bladder cancer model. We observed higher expression of the ectonucleotidases CD39 and CD73 in tumor cells and CD4(+) and CD8(+) T cells within the tumor microenvironment and peripheral circulation and upregulation of the adenosine receptors A2A and A2B in tumor cells, further confirming the activation of the adenosinergic pathway in this murine model. CD39 inhibition demonstrated no therapeutic benefits nor synergistic effect with anti-PD-L1 immunotherapy in tumor-bearing mice. On the contrary, CD73 inhibition reduced tumor progression and synergized with anti-PD-L1, leading to complete remission in 38 % of cases and a significant reduction in tumor mass in the remainder compared to anti-PD-L1 monotherapy. This combination resulted in favorable systemic immune modulation, including increased circulating CD4(+) and CD8(+) T cells and a decreased neutrophil-to-lymphocyte ratio. These findings suggest that the adenosinergic pathway limits the efficacy of anti-PD-L1 immunotherapy in invasive bladder cancer. Targeting the CD73 adenosinergic axis may enhance its effectiveness, offering a promising strategy to overcome resistance.	bladder
Variability in Health Care Utilization and Perioperative Outcomes Among Urinary Diversion Patients: Analysis of the National Surgical Quality Improvement Program Database.	INTRODUCTION: Bladder cancer (BC) urinary diversion (UD) outcomes remain the benchmark to which all other UDs are compared. However, a sizable proportion are performed for other invasive cancers or benign etiologies of the bladder. We aim to compare health care utilization (HU) and 30-day morbidity among benign and malignant UD etiologies. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was used to collect data on 20,885 patients who underwent UD for various indications: BC, gastrointestinal/gynecologic cancer (GC), radiation (R), interstitial cystitis/benign bladder, and neurogenic bladder/bowel (NGB; assigned using International Classification of Diseases codes). Risk-adjusted regression models were developed to identify predictors of HU, prolonged length of stay (PLOS), 30-day readmissions, discharge to continued care (DCC), and morbidity (30-day complications and mortality). Frailty was also compared among different etiologies using the 5-Item Frailty Index. RESULTS: Most patients had primary BC (91%, N = 19,060). GC had the highest complication rate (71%) and PLOS (50%), R had the highest readmission rate (23%), while NGB had the highest DCC (30%). GC was the least frail (≈14% with 5-Item Frailty Index ≥2) while NGB and R were the frailest (28% and 27%, respectively, P < .05). Moreover, frail radiated patients had the highest HU rate (81%, P < .001) while frail patients with GC had the highest complication rate (77%, P < .001). Compared with patients with BC, adjusted odds of PLOS, DCC, and 30-day complication rates significantly differed among UD etiologies (P < .05), except for interstitial cystitis/benign bladder. CONCLUSIONS: Postoperative HU and morbidity are greatly influenced by UD etiology. Care management in these vulnerable patient populations requires an individualized etiology-centered approach and cannot be benchmarked against those undergoing BC UD.	bladder
Mechanistic Insights and Future Directions for Enfortumab Vedotin in Urothelial Carcinoma: Highlights from the 10th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research Symposium.	Enfortumab vedotin (EV) in combination with pembrolizumab (P) has led to a new paradigm for the treatment of metastatic urothelial carcinoma (mUC). Since the presentation of the results of the EV-302 trial at the European Society of Medical Oncology 2023 annual meeting, the entire treatment landscape for mUC has been upended. At the 2024 Albert Symposium, we reviewed ongoing research investigating predictive biomarkers for EV response and resistance as well as clinical trials exploring the potential role for EV in different clinical disease states including non-muscle invasive and muscle-invasive disease.	bladder
Proteome-driven transcriptomic dissection of EMT networks in bladder cancer based on the VIM and CDH2 protein macromolecules influence: From molecular-protein subtyping to therapeutic target prioritization.	Bladder cancer progression is intrinsically linked to epithelial-mesenchymal transition (EMT), a protein-centric process driving metastasis and therapy resistance. This study systematically dissected bladder cancer transcriptomes through the lens of VIM (vimentin) and CDH2 (N-cadherin) protein networks, integrating datasets from GEO via cross-platform harmonization. Non-negative matrix factorization (NMF) resolved two molecular subtypes with distinct EMT-related protein expression profiles, characterized by asymmetric transcriptomic dysregulation. Functional enrichment revealed protein-driven pathways-including TGF-β signaling, Wnt/β-catenin activation, and ECM remodeling-as hallmarks of aggressive subtypes. LASSO regression identified 384 transcriptional drivers, while PPI network analysis prioritized 10 hub proteins (CALML5, THBS1, SMAD7, TAGLN, ICAM1, CEBPB, CNN1, TNFAIP3, TNFRSF1A, EFEMP2) via maximum clique centrality (MCC). Critically, TAGLN, CNN1, THBS1, and SMAD7 exhibited significant co-expression with VIM and CDH2 (correlation coefficients >0.1), implicating their roles in cytoskeletal protein assembly (TAGLN, CNN1), matricellular signaling (THBS1), and TGF-β pathway regulation (SMAD7). Functional validation confirmed these hub proteins as central to EMT plasticity, with TAGLN-VIM/CDH2 co-activation (r = 0.55 and 0.24, respectively) driving actin polymerization and protein-mediated invasion. SMAD7 further modulated TNFRSF1A-TNFAIP3 crosstalk to sustain mesenchymal phenotypes. This multi-omics framework delineates VIM/CDH2-centric protein interactomes as therapeutic vulnerabilities, proposing TAGLN/THBS1-targeted strategies to disrupt EMT-driven metastasis. By anchoring molecular subtyping and drug discovery in protein network topology, this work advances precision oncology for bladder cancer, bridging transcriptomic heterogeneity to actionable protein targets.	bladder
Microsatellite instability and mismatch repair deficiency in bladder urothelial carcinoma: a Tunisian single-center study.	BACKGROUND: Microsatellite instability (MSI) and deficiency in the human mismatch repair (MMR) system are critical drivers of genomic instability in various cancers. Tumors exhibiting MSI and MMR deficiency (dMMR) have prognostic implications and are associated with differential responses to immune checkpoint inhibitors. Given their key roles in tumorigenesis, investigating MMR protein expression and MSI in urothelial cancer of the bladder is essential to improve therapeutic strategies and deepen understanding of its molecular features. This study aimed to assess MMR protein expression and MSI in primary urothelial carcinoma of the bladder and to evaluate their associations with clinicopathological characteristics. METHODS: A total of 49 primary urothelial carcinomas were analyzed for MMR expression using immunohistochemistry, and dMMR tumors underwent further analysis for MSI status using the markers of the Bethesda panel (BAT25, BAT26, D2S123, D5S346, and D17S250). The MMR expression and MSI findings were associated with clinicopathological parameters. RESULTS: dMMR was identified in two high-grade urothelial carcinomas (4.1%), while the remaining cases demonstrated proficient MMR. Both dMMR tumors showed impaired immunoreactivity, with one tumor displaying a simultaneous loss of the MLH1/PMS2 heterodimer and the other showing isolated MSH6 loss. MSI analysis revealed instability in BAT26 in the MLH1/PMS2-deficient tumor and at D17S250 in the MSH6-deficient tumor. Both tumors exhibited low-level MSI (MSI-L). No relevant associations were found between MMR/MSI status and clinicopathological features (p > 0.05). CONCLUSIONS: The identification of MSI-L and MMR deficiency in only two samples underscores the rarity of MSI in urothelial carcinoma among Tunisian patients. These findings emphasize the need for larger, multi-center studies to elucidate the MSI/dMMR molecular and clinical implications in bladder carcinoma.	bladder
Phenotypic Diversity of Immunosuppressive B Cells Associated in Urothelial Carcinoma of the Bladder.	BACKGROUND: Urothelial carcinoma of the bladder presents a complex tumor microenvironment, with tumor-infiltrating B cells (TIL-Bs) playing a significant role in disease progression. Although their presence is acknowledged, the phenotypic diversity of regulatory TIL-Bs in bladder cancer remain underexplored. MATERIALS AND METHODS: In this study, we evaluated core B cell subsets and their immunosuppressive phenotypes in both peripheral blood (n=40) and bladder tumor tissues (n=40) to evaluate their relationship with disease severity. RESULTS: Our findings revealed that high-grade bladder tumors are enriched with B cells and their subsets, particularly transitional B cells and plasmacytes (plasmablasts and plasma cells). However, total memory B cells were reduced in the tumor microenvironment compared to non-tumor tissues. It was further revealed that the high-grade tumors demonstrated significant infiltration of regulatory B cells (Breg), with elevated levels of IL10+ and TGFβ+ Breg cells as well as IL-10+TGF-β+ dual-cytokine-secreting Breg cells, suggesting their role in fostering an immunosuppressive microenvironment. Memory B cells demonstrated the highest frequency of Breg phenotypes among the B cell subsets. Additionally, Tertiary Lymphoid Structure formation and frequency were associated with disease severity, the differentiated B cells and IL10+ Breg cell counts, emphasizing the importance of these structures in bladder cancer progression and the potential involvement in Breg cells formation. CONCLUSION: This study demonstrates the enrichment of the bladder cancer tumor microenvironment with diverse B cell subsets, including functional Breg cells, which correlates with disease severity.	bladder
Prognostic role of pathological substaging in high-grade pT1 bladder cancer undergoing BCG therapy: Insights on recurrence and progression.	INTRODUCTION/OBJECTIVES: Bladder cancer is a common malignancy, with pT1 tumors carrying a higher risk of recurrence and progression compared to other non-muscle-invasive bladder cancers (NMIBC). Substaging of pT1 tumors into superficial (pT1a) and deeper (pT1b) invasion into the lamina propria has shown potential prognostic value. This study investigates the impact of pT1 substaging on predicting progression and recurrence in patients with high-grade pT1 bladder cancer treated with Bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: A retrospective analysis was conducted on 99 patients with primary high-grade pT1 bladder cancer who underwent transurethral resection of the bladder tumor (TURBT) followed by BCG therapy. Patients were stratified into pT1a and pT1b subgroups based on pathological findings. Predictors of disease progression and recurrence were assessed using logistic regression, adjusting for age, tumor size, carcinoma in situ (CIS), and multiplicity. RESULTS: Of the 99 patients, 71.7% were classified as pT1a, and 28.3% as pT1b. Disease progression was significantly more frequent in pT1b cases (P < 0.001), particularly in the presence of concurrent CIS (P = 0.002). Logistic regression identified pT1b substaging (odds ratio [OR]: 28.9, 95% confidence interval [CI]: 12.4-58.7) and CIS (OR: 8.65, 95% CI: 3.21-18.8) as independent predictors of progression. DISCUSSION: Pathological substaging of pT1 bladder cancer provides critical prognostic insights. Patients with pT1b tumors, especially those with concurrent CIS, are at higher risk for disease progression and may benefit from intensified management strategies. Incorporating pT1 substaging into routine pathological evaluations can improve risk stratification and inform individualized treatment planning.	bladder
Metanephrine normal, DOTATATE negative paraganglioma of the urinary bladder.	A woman in her 30s presented with recurrent haematuria and dysuria for 1 year. Imaging revealed a 10 cm pedunculated mass in the bladder, with histopathology confirming paraganglioma. Initial management involved a transurethral biopsy of the tumour, followed by partial cystectomy with ureteric reimplantation. Six months later, she developed lower abdominal pain, and imaging revealed tumour recurrence. A second exploratory laparotomy was performed, confirming recurrent paraganglioma, for which wide local excision with adequate margins was done after a multidisciplinary team discussion comprising urologists, oncologists, radiologists and pathologists. Postoperative recovery was uneventful. Given the recurrent nature of the tumour, long-term follow-up with MRI and Gallium-68 DOTATATE PET-CT was recommended. 6 months later, the patient again developed a second recurrence, and she was advised pelvic exenteration after multidisciplinary tumour discussion. The patient party was not willing to consider this procedure, considering the high morbidity and mortality risk associated with the procedure. She succumbed to death soon after. Bladder paragangliomas are rare neuroendocrine tumours requiring early diagnosis and surgical intervention to prevent a recurrence. This case highlights the importance of histopathology, immunohistochemistry and long-term surveillance in managing bladder paragangliomas to optimise patient outcomes.	bladder
PD-L1 and Ki-67 Expression Before and After Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.	OBJECTIVE: Programmed cell death ligand 1 (PD-L1) expression is considered a poor prognostic factor in patients with muscle-invasive bladder cancer (MIBC). However, the data regarding the change in PD-L1 expression before and after neoadjuvant chemotherapy (NAC) are limited. We aimed to investigate the longitudinal association between programmed death-ligand 1 (PD-L1) and Ki-67 expression before and after NAC in muscle-invasive bladder cancer (MIBC). METHODS: We retrospectively analyzed 191 patients with MIBC who underwent platinum-based NAC followed by radical cystectomy (RC) between June 2010 and March 2022. We excluded ypT0-1 cases because of the difficulty of evaluating PD-L1 and Ki-67 by immunostaining. Finally, we selected 104 patients with matched specimens from transurethral resection of bladder tumor (TURBT) and residual invasive disease in RC. We examined the relationship between PD-L1 expression and Ki-67 labeling index in TURBT and RC specimens. Additionally, we investigated the differential expression of 39 subtype-related genes before and after NAC. RESULTS: Among 104 patients who underwent NAC, the number of PD-L1-positive patients significantly increased from 16 (15.4%) in the TURBT specimens to 30 (28.8%) in the RC specimens. The median Ki-67 labeling index significantly decreased from 30.6% in the TURBT specimens to 9.9% in the RC specimens. The correlation between treatment effects and changes in gene expression was challenging to identify. CONCLUSIONS: A significant effect of NAC on PD-L1 expression and Ki-67 labeling index was observed in patients with MIBC. However, the impact of changes in gene expression on prognosis needs further study.	bladder
Efficacy of brachytherapy for locally advanced bladder cancer: a single-center retrospective clinical study.	To explore the feasibility, safety, and effectiveness of brachytherapy of locally advanced bladder cancer, clinical data of 86 patients with locally advanced bladder cancer treated in the Department of Urology Surgery, Shanxi Provincial Cancer Hospital, between January 2015 and June 2019 were analyzed retrospectively. The patients were categorized into the study (n = 45) and control (n = 41) groups according to the treatment methods. Patients in the study group were treated with brachytherapy (intraoperative implantation of radioactive particles) + neoadjuvant chemotherapy (NAC), and those in the control group were treated with NAC. Patients in both groups underwent radical cystectomy (RC) + pelvic lymph node dissection. Postoperative pathological examinations proved that patients in both groups had urothelial carcinoma at stage pT(3)-pT(4). The endpoints included 3-y locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), and adverse events after treatment. The efficacy and safety of interstitial implantation of radioactive particles for the treatment of locally advanced bladder cancer were assessed. The patients were followed up for 9-42 months. The 3-y LRFS was significantly higher in the study group (88.9%) than in the control group (60.9%) (p = .003). The 3-y DMFS in the study group (71.1%) and the control group (73.2%) was statistically similar (p = .945). The 3-y DFS and OS were not statistically significant between the two groups (DFS: study group 64.4% vs. control group 51.2%, p = .073; OS: study group 66.7% vs. control group 58.5%, p = .180). Local shifting of the particles was detected in three patients at 1 week to 1 month after the operations in the study group, but no related complications were observed. Blood events (anemia, leukocytopenia, and thrombocytopenia), liver and renal dysfunction, vomiting, diarrhea, and weakness were the major adverse reactions, which were alleviated after symptomatic treatments. The results have not statistically significant differences between the two groups in major adverse reactions. Compared to the NAC group, brachytherapy + NAC significantly prolongs the LRFS of patients with locally advanced urothelial bladder carcinoma who underwent RC + pelvic lymph node dissection. This surgery increases the LRFS, develops better personalized treatment plans, and improves treatment effectiveness. In addition, the treatment is safe and effective, with only limited adverse effects.	bladder
Youth matters: a systematic review of the molecular and clinical landscape of bladder cancer in young adults.	BACKGROUND: Bladder cancer is uncommon in individuals under the age of 45, and its clinical and molecular characteristics in this population differ significantly from those observed in older patients. This systematic review aims to evaluate recurrence, progression, survival outcomes, and molecular profiles of bladder cancer in young adults. METHODS: A systematic search was conducted in MEDLINE, Embase, Scopus, and CENTRAL databases for studies published between 1998 and 2024. Eligible studies included patients aged ≤ 40 years and reported outcomes such as recurrence-free survival (RFS), progression, and overall survival (OS). A total of 18 studies were included. Risk of bias was assessed using the ROBINS-I tool, and pooled estimates were calculated using random-effects meta-analysis models. RESULTS: Bladder cancer in young adults is predominantly non-muscle-invasive and low-grade, with high survival rates. Recurrence rates varied across studies, ranging from 0 to 35.9%, while disease progression was rare. Several studies reported 100% RFS and OS in pediatric and young adult populations. The molecular profile of tumors in younger patients differed from that of older adults, with lower rates of TP53 and FGFR3 mutations. Meta-analysis revealed favorable long-term outcomes, particularly in patients diagnosed at early stages. CONCLUSION: Bladder cancer in young adults presents a distinct clinical and molecular entity with excellent prognosis, minimal progression, and high survival. Despite this, recurrence remains a concern, highlighting the need for age-specific surveillance strategies and further research into molecular drivers of the disease in this age group.	bladder
Nanoparticle-mediated targeting of PGC-1α reveals critical metabolic pathways in bladder cancer metastasis.	Metastatic bladder cancer is characterized by its aggressive behavior and complex molecular mechanisms that remain largely undefined. This study explores the therapeutic potential of targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) using liposomal nanoparticles to deliver PGC-1α siRNA to bladder cancer cells. We employed comprehensive transcriptomic, proteomic, and metabolomic analyses to investigate the impact of PGC-1α silencing. Our in vitro results demonstrate that targeting PGC-1α significantly impairs mitochondrial function and disrupts energy metabolism, affecting critical pathways such as glycolysis and the citric acid cycle, as well as altering mRNA nuclear export. In vivo experiments in animal models show that nanoparticles loaded with si-PGC-1α effectively reduce lung metastasis, indicating a significant impact on metastatic progression. These findings highlight PGC-1α as a key regulator of metabolic reprogramming in metastatic bladder cancer and suggest that its inhibition could serve as a promising therapeutic strategy. By elucidating the role of PGC-1α in cancer metabolism, this study provides new insights into the molecular underpinnings of bladder cancer metastasis and offers potential avenues for developing targeted therapies aimed at the metabolic vulnerabilities of this malignancy.	bladder
A study of oral metformin for the intravesical treatment of non-muscle-invasive bladder cancer.	OBJECTIVES: To evaluate the effect of metformin on non-muscle-invasive bladder cancer (NMIBC) marker lesions. PATIENTS AND METHODS: A phase II, open-label, multicentre, marker lesion trial using oral metformin in patients with primary or recurrent, multiple, low-grade Ta-T1 NMIBC was conducted. After transurethral resection for histological confirmation, leaving one tumour as a marker lesion, 11 patients were treated with oral metformin up to 3000 mg per day for 3 months. Reported outcomes included response of the marker lesion, safety of metformin, quality of life and pharmacological and immunohistochemical examinations of the mechanism of action of metformin. RESULTS: One complete response and one partial response were observed. In the other nine patients, the marker lesion remained, while five of these patients also developed new Ta low-grade lesions. Diarrhoea grade ≤ 2 was the most common adverse event (AE), observed in nine out of 11 patients. No serious AEs related to study treatment occurred. Metformin concentrations in the urine were significantly higher than metformin levels in the blood. Immunohistochemical analysis before and after treatment showed no difference in expression of markers associated with the mechanism of metformin. CONCLUSION: We did not find conclusive evidence for the hypothesis of an antitumour effect of metformin in bladder cancer.	bladder